Cancer is the leading or second most common cause of death in advanced countries. Despite continuing advances in both diagnosis and treatment regimens, most existing treatment methods have undesirable side effects and limited efficacy in treating and curing the cancerous diseases of solid tumors. Treatment of cancer is complicated by the variety and number of mechanisms involved in the formation and metastasis of tumors, many of which are still not well understood. Chemotherapy is, however, still one of the major options available for the first-line treatment in cancers such as leukemias and second-line treatment for refractory solid tumors. The mechanism of action of some effective anticancer agents remains unclear. Most of the currently used anticancer agents are small molecule chemicals and need to be administered into patients via a parenteral infusion or bolus injection. Clinical complications with the parenteral administrations have been documented and thus extra cares and cost for hospitalization are essential. Recent efforts in the discovery of anticancer drugs have been focused on finding orally active anticancer agents.
Angiogenesis refers to the generation of new blood vessels into a tissue or organ. Under normal physiological conditions, humans or animals only undergo angiogenesis in very specific restricted situations. For example, angiogenesis is normally observed in wound healing, fetal and embryonal development and formation of the corpus luteum, endometrium and placenta. The control of angiogenesis is a highly regulated system of angiogenic stimulators and inhibitors. The control of angiogenesis has been found to be altered in certain disease states and, in many cases, the pathological damage associated with the disease is related to uncontrolled angiogenesis. Thus, methods and compositions are needed that are capable of inhibiting angiogenesis and which are easily administered. A simple and efficacious method of treatment would be through the oral route, which could be distributed in a form that the patient could self-administer.
The invention presents heterocyclic compounds that exhibit cytotoxic and anticancer activity and that inhibit angiogenesis.